High expression of APC is an unfavorable prognostic biomarker in T4 gastric cancer patients

Abstract

Background: Adenoma polyposis coli (APC) mutation is associated with tumorigenesis via the Wnt signaling pathway.

Aim: To investigate the clinical features and mechanism of APC expression in gastric cancer (GC).

Methods: Based on APC expression profile, the related genome-wide mRNA expression, microRNA (miRNA) expression, and methylation profile in GC, the relationship between APC and GC, as well as the prognostic significance of APC were systematically analyzed by multi-dimensional methods.

Results: We found that high expression of APC (APC ^high) was significantly associated with adverse outcomes of T4 GC patients. Genome-wide gene expression analysis revealed that varying APC expression levels in GC were associated with some important oncogenes, and corresponding cellular functional pathways. Genome-wide miRNA expression analysis indicated that most of miRNAs associated with high APC expression were downregulated. The mRNA-miRNA regulatory network analysis revealed that down-regulated miRNAs affected their inhibitory effect on tumor genes. Genome-wide methylation profiles associated with APC expression showed that there was differential methylation between the APC ^high and APC ^low groups. The number of hypermethylation sites was larger than that of hypomethylation sites, and most of hypermethylation sites were enriched in CpG islands.

Conclusion: Our research demonstrated that high APC expression is an unfavorable prognostic factor for T4 GC patients and may be used as a novel biomarker for pathogenesis research, diagnosis, and treatment of GC.

Keywords: Adenoma polyposis coli; Gastric cancer; Methylation; Prognosis; mRNA; miRNA.

Figure 1

Prognostic value of APC expression in gastric cancer patients. A: Overall survival of gastric cancer patients with high APC expression and those with low expression (based on median value); B: Relapse-free survival of gastric cancer patients with high APC expression and those with low expression; C: Distribution of APC expression; D: Relapse-free survival of T4 gastric cancer patients with high APC expression and those with low expression. APC: Adenoma polyposis coli; GC: Gastric cancer.

Figure 2

Differentially expressed mRNAs associated with APC^high. A: Volcanic map of differentially expressed mRNAs associated with APC^high; (B) Heatmap of differentially expressed mRNAs associated with APC^high. APC: Adenoma polyposis coli.

Figure 3

KEGG pathways of differentially expressed mRNAs associated with APC^high. Upregulated pathways of (A) cell receptor signaling and (B) pancreatic cancer and downregulated pathways of (C) ascorbate and aldarate metabolism and (D) PPAR signaling pathway are shown. APC: Adenoma polyposis coli.

Figure 4

Genome-wide analysis of miRNAs associated with APC^high. A: Relationship between the correlation coefficient and correlation P-value; B: MiRNAs that were significantly positively correlated (red), negatively correlated (green), and had no correlation (blue) with APC^high, as well as the heatmap of miRNAs associated with APC^high; C: mRNA-miRNA regulatory network. APC: Adenoma polyposis coli.

Figure 5

Differential expression of DNMT1, DNMT3A, and DNMT3B between APC^high and APC^low. APC: Adenoma polyposis coli; DNMT: DNA methyltransferase.

Figure 6

Analysis of relationship between APC^high and genome-wide DNA methylation. A: Volcanic map of differential DNA methylation associated with APC^high; B: Distribution of DNA methylation associated with APC^high based on CPG islands; C: Distribution of DNA methylation associated with APC^high based on transcription initiation site; D: Upregulated KEGG pathways of genes corresponding to the nearest transcription initiation site of differential DNA methylation; E: Downregulated KEGG pathways of genes corresponding to the nearest transcription initiation site of differential DNA methylation. APC: Adenoma polyposis coli.